The invention relates to compositions of a dispersion comprising amorphous drug and a matrix combined with a concentration-enhancing polymer that improves the stability of the drug and/or enhances the concentration of the drug in a use environment.
Low-solubility drugs often show poor bioavailability or irregular absorption, the degree of irregularity being affected by factors such as dose level, fed state of the patient, and form of the drug. Increasing the bioavailability of low-solubility drugs has been the subject of much research. Increasing bioavailability hinges on improving the concentration of the drug in solution to improve absorption.
It is well known that the amorphous form of a low-solubility drug that is capable of existing in either the crystalline or amorphous form may temporarily provide a greater aqueous concentration of drug relative to the equilibrium concentration obtained by dissolution of drug in a use environment. Such amorphous forms may consist of the amorphous drug alone, a dispersion of the drug in a matrix material, or the drug adsorbed onto a substrate. It is believed that such amorphous forms of the drug may dissolve more rapidly than the crystalline form, often dissolving faster than the drug can precipitate from solution. As a result, the amorphous form may temporarily provide a greater-than equilibrium concentration of drug.
While such amorphous forms may show initially enhanced concentration of the drug in a use environment, nevertheless the improved concentration is often short-lived. Typically, the initially enhanced drug concentration is only temporary and quickly returns to the lower equilibrium concentration.
One approach to increase the bioavailability of low-solubility drugs has involved forming amorphous dispersions of drugs with polymers. Examples of attempts to increase drug concentration by forming a dispersion of the drug with a polymer include Lahr et al., U.S. Pat. No. 5,368,864, Kanikanti et al., U.S. Pat. No. 5,707,655, and Nakamichi et al., U.S. Pat. No. 5,456,923.
Curatolo et al., EP 0901786A2, disclose solid amorphous dispersions of poorly water soluble drugs and hydroxypropylmethyl cellulose acetate succinate (HPMCAS). In one embodiment, HPMCAS is a dispersion polymer. Alternatively, a dispersion may be formed of a drug and conventional matrix material such as PVP, HPC or HPMC and then the dispersion is triturated with HPMCAS.
One problem with using the amorphous form of a drug is that the solid drug may not be stable physically in the amorphous form. Often the crystalline form of the drug has a lower free energy, and thus over time, the amorphous drug will tend to crystallize. The rate of crystallization may be influenced by storage conditions, such as temperature and humidity, as well as the constituents of the composition.
Similarly, even if a dispersion of drug and polymer is formed, the drug in the resulting amorphous dispersion of polymer and drug may in some cases be unstable. For example, the dispersion may be physically unstable, causing the amorphous drug to separate from the dispersion and/or crystallize. Alternatively, the drug in the amorphous dispersion may be chemically unstable. The drug may degrade over time at moderate temperature and humidity levels or the drug may convert to a lower energy and lower solubility amorphous or crystalline form.
Alternatively, it may be difficult or, in some cases, impossible to form a dispersion of the drug and preferred polymer. In particular, the drug and preferred polymer may not both be amenable to a processing method that results in a dispersion of the drug and preferred polymer. For example, when solvent processing is the preferred method for forming the dispersion, the drug and preferred polymer may not both be soluble to a sufficient extent in an appropriate processing solvent to allow formation of the dispersion. In cases where melt processing is preferred, the drug or polymer or both may suffer unacceptable decomposition upon heating to allow the formation of the preferred composition to be practical.
Accordingly, what is still desired is a composition comprising an amorphous drug that is physically and/or chemically stable under typical storage conditions, may be formed via practical processing conditions, and that may enhance the bioavailability of poorly soluble drugs. These needs and others that will become apparent to one of ordinary skill are met by the present invention, which is summarized and described in detail below.